The human tear provides a protective film that covers the ocular surface, thereby preventing ocular discomfort and damage to the ocular surface. A healthy human tear film consists of a delicate balance of three layers, namely, the outermost lipid layer, the innermost mucin layer adjacent to the ocular surface, and the middle aqueous layer. The lipid layer, the outermost layer of the tear film, seals the tear film to prevent evaporation and maintain the structural integrity of the tear film. The lipid layer is produced by the meibomian glands found in the eyelids. The aqueous layer, the middle layer of the tear film, functions to cleanse the eye and deliver oxygen to the avascular cornea, and to provide other nutrients and protectants to the eye, including immune-system proteins that help prevent microbial or toxic substances from reaching the ocular surface. The aqueous (watery) layer is produced primarily by the lacrimal glands. The mucin layer, which is the innermost layer adjacent the ocular surface, is produced by the goblet cells of the conjunctiva and cornea. The mucin layer serves to coat the hydrophobic corneal epithelium with a hydrophilic layer. The mucin layer helps the aqueous layer spread over the ocular surface and allows the surface to become hydrophilic. The mucin layer contributes to maintaining hydration of the ocular surface and preventing pathogens from reaching the ocular surface.
The three layered tear film is critical in maintaining the integrity of the tear film, which, in turn, maintains the integrity of the ocular surface. A compromised tear film can cause drying of the ocular surface. The condition of dry eye syndrome, medically known as keratoconjunctivitis sicca (KCS), is the term for a number of clinical disease states characterized by disturbances in the pre-ocular tear film resulting in ocular surface disease. KCS accounts for the highest percentage of patient visits to ophthalmologists, and its treatment has given rise to a global pharmaceutical market of over 3 billion dollars.
Dry eye syndrome can originate from a variety of causes. In the report of the National Eye Institute/Industry Workshop on Clinical Trials in Dry Eyes issued in 1995, a new classification system for the various types of dry eye syndrome was presented. The two major categories are:
I. Evaporative Type
One cause of this type is meibomian gland dysfunction, which leads to a deficiency and/or alteration in the lipid layer of the tear film, and the resulting premature evaporation of the tear film. Contact lens wear also contributes to evaporative KCS and this is a double-edge sword, as a lipid deficient dry eye will also act to prevent many people from comfortably wearing of contact lenses. Blinking abnormality also leads to evaporative KCS. The mucin layer also plays a major role in this classification, as the mucus must provide wettability directly on the epithelial cells of the cornea and conjunctiva, which is greatly improved by a higher oncotic pressure, optimally greater than 45 mmHg.
II. Aqueous Tear Production Deficient Type
There are two primary subcategories of the aqueous tear production deficient type. The first subcategory, Non-Sjögren's Associated KCS, is by far the most common. It is caused by a decrease in lacrimal glands secretions due to numerous factors, including but not limited to old age, and the use of certain medications such as oral antihistamines and antidepressants, which can cause ocular dryings as a side effect. The second subcategory, Sjögren's Associated KCS, is related to the autoimmune disease Sjögren's Syndrome, which involves the body's immune system turning against the host. As related to KCS, Sjögren's Syndrome causes permanent damage to the lacrimal glands, resulting in a deficiency in tear production. Patients with Sjögren's Syndrome also experience dry mouth, dry skin, vaginal dryness and, in 20% of the cases, rheumatoid arthritis.
Each time a person blinks the tear film is reformed and, therefore, remains intact. A primary goal of treating KCS is to achieve an extension in the time the tear film remains intact after a blink. As the eye remains open after a blink, at some duration of time as the eye remains open, the tear film will breakup and the ocular surface will become exposed and unprotected until the next blink. It can be appreciated that even minute differences in the duration of tear film integrity can make a difference in the clinical profile of a KCS patient, because the repeated intermittent exposures can lead to ocular surface damage. Thus, a primary goal of dry-eye therapies is to achieve an extension in the time the tear film remains intact.
A mainstay in the treatment of KCS is the use of artificial tear formulations. Currently, approximately 35 million people, worldwide require the use of artificial tear formulations. An ideal artificial tear formulation would be able to achieve a lengthening of tear film breakup time while also being comfortable in the eye. A tear substitute needs to provide sufficient reduction of tear film breakup to bridge the gap between the tear film breakup time and time between blinks, in order to provide improved ocular surface protection. At the same time, the tear substitute also needs to be comfortable in the eye.
Commercially available artificial tear formulations do not adequately replicate all three layers of the normal human tear film. Numerous research supports the importance of the lipid layer, with one of the most significant studies by Drs. Heiligenhaus, Koch, Kruse, Schwarz and Waubke at the University of Essen Eye Clinic (Germany), in which 110 dry eye patients were examined. All patients had moderate to severe KCS, documented by well accepted methods, and not controlled with commercially available artificial tear products, with the following findings:                8% had aqueous deficiency        26% had disturbances in two or more layers        78% had lipid deficiencyAdditional research by Drs. Craig and Tomlinson of the Glasgow Caledonian University Department of Vision Sciences (Scotland) studied the left eyes of 161 normal and dry eye subjects with sensitive measurement of tear evaporation, demonstrating the following conclusion: “Where the human lipid layer is absent, or is not confluent, and the tear film is unstable, tear evaporation is increased four-fold. However, where there is a stable, intact lipid layer, regardless of lipid thickness, tear evaporation is retarded.”        
Despite the demonstrated importance of artificial tear formulations replicating all three layers of the normal human tear film, the vast majority of artificial tear preparations only contain certain polymers, such as one of the cellulose ethers and/or polyvinyl alcohol, in an attempt to mimic the mucin layer; along with purified water for mimicking the aqueous layer, but very few attempts have been made to incorporate a lipid component as well, and none of the latter have been a commercial success, to date. The need exists for an artificial tear formulation that replicates all three layers of the normal human tear film.